Close to 70% of kidney stones are composed partially or predominantly of calcium oxalate. There is no satisfactory drug specific for the treatment of calcium oxalate urolithiasis, nor for prophylactic use by people prone to recurrent attacks of this disease.
Common procedures for treatment of renal lithiasis due to calcium oxalate consist of surgical removal of stones, or control of the diet to restrict intake of calcium and/or oxalate combined with ingestion of large quantities of water to dilute the urine. Attempts at chemotherapy have included the administration of magnesium oxide, orthophosphate, cellulose phosphate, isocarboxazide, thiazide diuretics, allopurinol and succinimide. Limited success has been realized so far by these drug approaches. No drug which specifically inhibits the biosynthetic formation of oxalic acid is available for the treatment of calcium oxalate renal lithiasis.
The immediate metabolic precursor of the majority of the oxalate in human urine is glyoxylic acid. Much of the glyoxylic acid is, in turn, derived from glycolic acid. The enzyme glycolate oxidase (GAO) is known to carry out the oxidation of glycolic acid, through glyoxylic acid, to oxalic acid. Inhibition of this enzyme will therefore lead to a reduction in the concentration of oxalic acid in the kidney and bladder, reducing the probability that calcium oxalate crystallization will occur. Thus inhibitors of glycolate oxidase provide a specific approach to the prevention and treatment of calcium oxalate lithiasis.